[unreadable] This proposal for a K18 Career Enhancement Award for Stem Cell Research describes a one year training program which will allow the principal investigator (PI) to appropriately use stem cells in his research on Hepatic Tissue Engineering. The PI, Dr. Martin Yarmush, is an MD PhD bioengineer who for the past 15 years has been developing critical technologies for bioartificial liver support systems. A critical issue in the development of bioartificial liver support systems is the limited availability of large numbers of differentiated hepatocytes necessary to seed these devices. As a means of addressing this problem, the PI has gravitated towards stem cell engineering, specifically focusing on directing embryonic stem cell differentiation into hepatocytes. After some initial work of an empirical nature, the PI seeks more focused training in developmental and stem cell biology. Through a program of didactic coursework, seminars and research, the PI will focus his efforts on embryonic stem cell biology. Dr. George Q. Daly, an internationally recognized stem cell expert will serve as the sponsor. The PI will become intimately familiar with many of the techniques that Dr. Daley's lab has developed related to self-renewal and differentiation of human ES cells, and then apply them to directing ES cells to mature hepatocytes. The research focus in this proposal is to develop techniques to derive adult hepatocytes from embryonic stem (ES) cells in vitro. For the purpose of developing the technology and gaining a better understanding of the underlying basic science, a mouse model will be used. The overall goals of this project are two-fold: (1) to develop an approach to reset the clock of diseased adult hepatocytes to a progenitor stage, and (2) to understand the molecular mechanisms of switching between proliferation and differentiation in progenitor cells, so that higher levels of liver-specific functions can be expressed in the differentiated hepatocytes. Through this work, we hope to produce a clonal source of hepatocytes which could be used in various applications of hepatic tissue engineering, including drug screening, toxicology, and bioartificial liver assist devices. The Childrens Hospital Boston, the Center for Engineering in Medicine at MGH, the Harvard Stem Cell Institute with its distinguished faculty, interdisciplinary environment, well equipped core facilities, and extensive collaborative interactions will provide the PI with everything necessary to pursue his goals. [unreadable] [unreadable]